Method of preparing a tetracycline type antibiotic-containing wound dressing



United States Patent METHOD OF PREPARING A TETRACYCLINE TYPEANTIBIOTIC-CONTAINING WOUND DRESSING Frank Edwin Stirn and Jens ThuroeCarstensen, Pearl River, N. Y., assignors to American Cyanamid Company,New York, N. Y., a corporation of Maine No Drawing. Application April24, 1951, Serial No. 222,730

1 Claim. (Cl. 167-84) This invention relates to a wound dressingsatisfactory for surface wounds, for example burns, abrasions, skingrafting sites, or after surgery. We have prepared a sterile dressingconsisting of a broad-spectrum tetracycline type antibiotic in ananhydrous ointment base, which forms a water-in-oil emulsion, on a gauzedressing or other backing and which can be applied directly to a wound,and may be stored, ready for instant use, in a sealed sterile container.Our invention also includes the method of preparation of the dressing,and the container for the dressing.

In the past it has been frequently customary to spread a petroleum jellyon a sterile gauze for application to a wound such as a burn.Unfortunately petroleum jelly does not absorb moisture and isincompatible with aqueous fluids, and causes maceration. A wound hassmall accumu lations of moisture that support bacterial growth andinterfere with healing underneath the dressing and as a result thedressing must be changed and healing is retarded.

We have prepared a sterile, sealed package containing a carrier for anointment, which ointment is essentially anhydrous. The ointment is aspecial type which, on admixture with water, forms a water-in-oilemulsion, thereby providing. a wound dressing which (1) keeps the wounddry, (2) minimizes maceration, (3) releases a broadspectrum tetracyclinetype antibiotic over a long period, and (4) minimizes the adherence ofthe dressing to the wound. Because plasma or other aqueous fluid isabsorbed into the emulsion to form a cream and is removed from thewound, the wound is kept sterile, clean, and dry, and therefore healsmore rapidly than has been possible with previously known types ofdressings.

The backing or carrier for our ointment may be a surgical gauze ofcotton, nylon, cellulose acetate, etc., or may be a more tightly wovencloth, or may bean absorbent cotton, preferably felted, or other unwovenfabric, or may be of a plastic material, as for example, an oilresistant synthetic rubber or porous plastic or other material. It ispreferred that the mesh be fairly fine to reduce the possibility oftissue growth through the interstices. We normally prefer a cotton gauzewith about a 44 x 36 inch thread count because it has met with thegreatest acceptance by the medical profession, is a standard commercialitem and is very economical. Such a gauze is very soft and flexible andmay be removed from the wound with a minimum of lint being left. Whereaswe prefer such gauze, it is to be understood that other types ofcarriers may be used where desired.

Whereas most dispersing agents tend to produce an oilin-water type ofemulsion, we have found that we can obtain a reversed type of emulsionby using anhydrous lanolin, preferably acid washed lanolin, and adispersing agent such as glyceryl monostearate or a cholesterol ester.Glyceryl monostearate is economical and available, but other glycerylmono-esters of long chain fatty acids are good dispersing agents.Glyceryl monolaurate is another useful commercially available suchdispersing agent. The glyceryl monostearate and anhydrous lanolin shouldbe suspended in an oil base. We prefer a mixture of white or yellowpetrolatum and mineral oil together with a wax such as ceresin wax orbeeswax or parafiin wax. Agar plate tests show that broad-spectrumtetracycline type antibiotics in the ointment diffuse slightly morerapidly when ceresin wax is used rather than beeswax or parafiin wax.The ratios of the petrolatum, the mineral oil and the wax should bechosen so that when combined with the dispersing agent and the anhydrouslanolin, there is obtained an ointment base which is fluid at justslightly above body temperatures. The preparation may melt between about33 and 44 C. and preferably between 37 and 43 C. Those skilled incompounding can adjust the proportions of the mineral oil, thepetrolatum and the wax so that the melting point is within this desiredrange.

Our ointment may be compounded with any of the broad-spectrumtetracycline type antibiotics, or mixtures of them, in a therapeuticallyuseful form. The first discovered of the tetracycline type antibioticswere chlortetracycline and oxytetracycline. A broad-spectrum antibioticsuch as chlortetracycline may be present as a salt with an acid, such asthe hydrochloride salt or the sulfate, as a free base, or a salt with ametallic or nitrogen base or any other stable therapeutically efiectiveform such as the lauryl sulfate or aluminum glycinate salts. We normallyprefer to use chlortetracycline hydrochloride as it is readily availablecommercially and is a form of such a broad-spectrum antibiotic which maybe easily and conveniently micropulverized, stored, and utilized. Theexact degree of pulverization may vary but a satisfactory form ofdispersion is found to be one in which approximately 35% by weight iswithin the range of 5 to 10 microns, approximately 60% within the rangeof 3 to 5 microns and approximately 5% less than 3 microns.

The ointment may be spread on the carrier, and the finished dressing,such as gauze with the ointment, stored in a suitable sterile container.We have found that an aluminum foil container which is laminated on theinside to a film of a copolymer of vinyl chloride and vinyl acetate by asuitable adhesive, provides a heat scalable coating on the inside of thefoil and gives a readily scalable sterile envelope.

In the preparation of our product we prefer to use a. surgical gauze,such as a boiled and bleached gauze of 44 x 36 thread count, whichnormally contains 6 or 7% of moisture. It may be placed in the aluminumfoil envelope which is sealed on three sides and sterilized while openon one end at a temperature of approximately C for 10 hours, which driesand sterilizes both the gauze and the envelope.

We prefer to mix the glyceryl monostearate, anhydrous lanolin and whitepetrolatum and ceresin wax, and if desired, a portion of the mineraloil, by blending them together in an ointment mill until they arethoroughly intermixed and then sterilize them at a temperature of 110 C.for 10 hours. Separately, chlortetracycline hydrochloride ismicropulverized and homogenized with the mineral oil, or rest of themineral oil, and the mixture sterilized at 110 C. for 10 hours. The twoparts of the ointment may then be mixed under aseptic conditions so asto maintain their sterility, and the required amount of the sterilefinished ointment is then applied to the sterile gauze in the aluminumfoil envelope while maintaining sterility. The air may then be pressedout of the envelope and the envelope sealed along the open edge by asealing machine at a suitable temperature, such as about 200 C. Afterthe ointment is added to the gauze in the envelope and the envelopesealed, it may then be uniformly heated to about 50 to 60 C. and theenvelope rolled while warm lightly but firmly once or twice at rightangles so as to distribute the ointment uniformly over the gauze.

We also 'find that our ointment may be melted, and while maintainedmelted, the gauze or other carrier may be passed through the liquid soas to impregnate the carrier. The temperature of the liquid and speedwith which the gauze or carrier ispassed through, and the nature of thecarrier determines the amount of ointment on the carrier. A fine meshgauze will carry'more ointment than a coarse mesh gauze. A doctor bladeor squeegee may be used to assist in the control of the amount applied.These operations should be carried out sterilely so that the continuousgauze strip thus formed may be cut intosegments and packedsterilely'into containers.

The final product is sterile and gives a chlortetracyclin'e-containingointment which maybe used to treat a wound. As the chlortetracycline isreleased into the tissue fluid, the ointment base permits the diffusionof aqueous fluids. Any ointment which' rem ains afterjuse' of thedressing can be removed from the surface'of-the wound by washing withwater. i

It is found that the inhibitionof bacterial growth on an agar plate withourrdressing is much'greater than that obtained byconventional types ofdressings, as' our dressing permits diffusion of the antibiotic to a fargreater extent than conventional dressings.

Our product may be maintained at 56 C; for two weeks without appreciabledestruction of the chlortetracycline. This corresponds to between twoand three years aging under normal storage conditions and proves thatthe product is storage stable under normal corn-,

mercial conditions of use.

The exact composition of the burn dressing ointment may vary over ratherwide limits. For example, the glyceryl monostearate may be present inproportions from 1 to 10%, the lanolin from 5 to 20%, the petrolatumfrom to 30%, the .wax from 5 to 20% the'mineral oil from 30 to 60% andthe chlortetracycline from 0.1 to 5%. The variation in the variouscomponents is .such that the sum totalis 100% and the melting point isbetween 33 and 44 C., preferably-between 37 and 43 C. Adjusting thequantity of wax is particularly effective in adjusting the melting pointto the desired limits.

Inthe formulation of the product, the broad-spectrum tetracycline typeantibiotic may be ground to the desired particlesize before it is mixedwith the mineral oil, or it may be ground in the mineral oil.

The broad-spectrum tetracycline type antibiotics, such aschlortetracyclinehydrochloride, seem to .control undesired bacterialgrowth and it .has been demonstrated clinically that the use of ourointment in a dressing causes the destruction of .hemolytic organismsresponsible. for.

delaying thehealing of wounds and for preventing the take of skingrafts. The dressing may be eitherused 'on a wound which has presentsuch bacterial growth to control thegrowth, or as a prophylactic measureon clean wounds to inhibit and prevent undesired bacterialgrowth. Suchmaterials as the alkyl esters of para-hydroxybenzoic acid may beincorporated with the broad-spectrum antibiotic if the growth of moniliais a problem.

Unlike so many of the sulfa drugs and previously used materials, thebroad-spectrum tetracycline type antibiotics do not interfere with woundhealing or epithelialization. Theeffect ofthe broad-spectrumtetracycline type antibiotics, such .as chlortetracycline hydrochloride,is most amazing and the increased speed of wound healing may be in factpartly due to the antibiotic itself. The dressing usually does notadhere to the wound even if left for one or two weeks without beingdisturbed and during this time maintains a high concentration of theantibiotic. With chlortetracycline, a concentration is obtained which issufiicient to control the growth of even such resistance organisms asProteus.

The quantity of the ointment used on the dressing may vary over widelimits. We find that from to milliliters of ,the ointment provides avery satisfactory coating for an 8 x .12 inch single layer surgicalgauze bandage. A much lesser amount may be used for thinner bandages orless serious wounds, and a greater quantity may be used with a multiplelayer bandage or where the impregnated layer forms part of a multiplelayer bandage.

We find that a single layer bandage prepared in accordance with ourinvention may be removed from its sterile container and placed incontact with the surface of the wound and then backed by surgicalsponges or multiple layers of gauze bandages, and then wrapped with anelastic bandage to serve as a pressure dressing. Such a dressing on evendeep burns may be left in place for a week or two and at the end of thattime most wounds will have been found to have completely healed.

By way of illustration, but not limitation, certain examples of ourinvention are herewith set forth.

EXAMPLE 1 Ointment 5 grams of glyceryl .monostearate, 10 grams ';Of anhydrous lanolin, U. S. P., 20.grams of white petrolatum, U. S. P., and15 grams of refined ceresin wax .be mixed in an ointment mill at atemperature of 100 C. until a smooth, thin, homogeneous mixture isobtained. The mixture may then be heated at 110C. for l0hours.

Separately, there is prepared a mixture of .49 grams of mineral oil -U.S. P. and 1 gram of chlortetracycline hydrochloride which has beenmicropulverized. The chlortetracycline hydrochloride is mixed with themineral oil, then sterilized at 110 C. for 10hours.

The two sterile mixtures are mixed under aseptic conditions at roomtemperature untila smooth, homogeneous ointment is obtained. Theointment is stored sterilely and handled sterilely throughout.

EXAMPLE 2 Complete dressing A single layer-8 x 12 inch gauze dressing ofa 44x 36 thread count may be folded in accordance with usual proceduresand-fitted into 8.3 x 4 inch envelope prepared from a thermosealingplastic-lined aluminum foil sealed together on three-sides. The foldedgauze in the envelope is sterilizedv at 110 C. for '10 hours which driesand sterilizes both the gauze and the-envelope. Aseptically there ,maybe then added 15 milliliters of the ointment preparedin accordance withthe preceding example. The envelope is then sealed along the openedge.

The ointment may be evenly dispersed throughout the dressing by heatingthe sealed envelope to 55 C. and

needed for use.

rolling twice in each direction with a rollingpin. The ointment in thedressing as thus prepared is evenly dispersed and the dressing is readyfor application to a burn or other wound. The envelope may be storeduntil At the time of use the foil envelope should be torn open and thebandage removed under sterile conditions and applied to the wound.

EXAMPLE 3 3 grams of crystalline chlortetracycline hydrochloride may beground in 30 gramsof mineral oil until the chlortetracyclinehydrochloride is pulverized to a particle size predominantly betweenabout 3 and .10 microns. The pulverized material inthe mineral oil isheated at C. for 10 hours. A second sterile mixture may be preparedcontaining 5 grams of glyceryl monostearate, 10 grams of anhydrouslanolin, 20 grams of white petrolatum, 15 grams of ceresin wax and 27grams of mineral oil. This mixture is ground in an ointment mill untilhomogeneous and then sterilized at 110 C. for 10 hours. The two sterilemixtures are combined under aseptic conditions at room temperature toprovide a smooth homogeneous sten'le ointment. 'The ointment-maybeheated to 50 C. and therethrough passed a continuous surgical gauzeapproximately 4" wide. The amount of ointment on the gauze may becontrolled bypassing the dressing between rolls. The ointment may beapplied at the rate of approximately 1 milliliter to each square inchesofthe dressing. The dressing may be then stored in a sterile jar untilready for use.

EXAMPLE 4 5 grams of glyceryl monostearate, grams of anhydrous lanolin,20 grams of white petrolaturn and grams of refined ceresin wax may bemixed in an ointment mill until a smooth homogeneous mixture isobtained, and then sterilized at 110 C. for 10 hours. Separately, theremay be sterilely prepared a mixture of 47 grams of sterile mineral oiland 3 grams of sterile oxytetracycline hydrochloride which has beenmicropulverized. The oxytetracycline is mixed with the mineral oil andto this sterile mixture there is sterilely added the mixture aboverecited. The sterile mixture may then be added to a gauze dressing atthe rate of A of a milliliter per square inch and the dressing stored ina sterile container until ready for use.

EXAMPLE 5 1,650 grams of micropulverized chlortetracycline hydrochlorideare suspended in about liters of mineral oil in a colloid mill set at0.002. The mixture may then be heated to sterilize it. A second mixturemay be prepared containing 11,550 grams of anhydrous lanolin, 17,325grams of ceresin wax, 23,100 grams of White petrolatum, 5,775 grams ofglyceryl monostearate and the remainder of sufficient light liquidpetrolatum so that a total of 90,600 grams are present in both mixtures,the mixture stirred until homogeneous, and then sterilized. The twomixtures may then be blended, preferably at room temperature and appliedto surgical gauze at the rate of approximately /5 of a milliliter persquare inch. The thus prepared gauze may be cut into individualbandages, sterilely inserted into foil containers and the individualfoil containers sealed. The thus prepared wound dressing may besterilely stored in the hermetically sealed foil containers until readyfor use.

The ointment itself is described in greater detail and claimed in ourco-pending application, Serial No. 222,729 filed April 24, 1951.

Where percentages are specified in the appended claim, such percentagesare based upon the final ointment composition which is applied to thecarrier.

As our invention we claim:

The method of preparing an anhydrous, storage stable, sterile,broad-spectrum antibiotic-containing Wound dressing which comprisesmixing from 1 to 10% of glyceryl monostearate, from 5 to 20% ofanhydrous lanolin, from 10 to 30% of petrolatum, from 5 to 20% of wax,and from 0% to about 25% mineral oil, and sterilizing the mixture byheating, separately mixing and sterilizing by heating from 0.1 to 5% ofa micropulverized broadspectrum tetracycline type antibiotic insufiicient mineral oil so that a total of from 30 to of mineral oil ispresent, the proportions being such that the melting point of the finalmixture is between 33 and 44 C., sterilely mixing together the two thusprepared sterile mixtures, inserting a folded gauze carrier in ascalable foil envelope under non-sterile conditions, heat sterilizingsaid folded gauze carrier in said envelope together with the envelope,adding the sterile mixture sterilely to said sterile scalable foilenvelope having therein said sterile gauze carrier, sealing saidenvelope, and dispersing the mixture uniformly over said carrier.

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